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Diacylglycerol O-acyltransferase 2, a Novel Target of Flavivirus NS2B3 Protease, Promotes Zika Virus Replication by Regulating Lipid Droplet Formation

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Specialty Biology
Date 2024 Oct 25
PMID 39449854
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Abstract

Various lipid metabolism-related factors are essential for Zika virus (ZIKV) replication. In this study, we revealed a crucial role of diacylglycerol O-acyltransferase 2 (DGAT2) in ZIKV replication using a short hairpin RNA-based gene knockdown technique. The replication of ZIKV was significantly inhibited by DGAT2 depletion in multiple cell lines and restored by trans-complementation with DGAT2. Mechanistically, DGAT2 is recruited in the viral replication complex by interacting with non-structural (NS) proteins. Among them, both human and murine DGAT2s can be cleaved by NS2B3 at the R-R-S site. Interestingly, the cleavage product of DGAT2 becomes more stable and is sufficient to promote the lipid droplet (LD) formation independent of its enzymatic activity. This work identifies DGAT2 as a novel target of the viral protease NS2B3 and elucidates that DGAT2 is recruited by viral proteins into the replication complex, thereby playing a proviral role by promoting LD formation, which advances our understanding of host-flavivirus interaction.

References
1.
Li W, Li N, Dai S, Hou G, Guo K, Chen X . Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA. FASEB J. 2019; 33(9):9929-9944. DOI: 10.1096/fj.201900260R. View

2.
Lazear H, Diamond M . Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere. J Virol. 2016; 90(10):4864-4875. PMC: 4859708. DOI: 10.1128/JVI.00252-16. View

3.
Heaton N, Perera R, Berger K, Khadka S, LaCount D, Kuhn R . Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A. 2010; 107(40):17345-50. PMC: 2951450. DOI: 10.1073/pnas.1010811107. View

4.
McFie P, Stone S, Banman S, Stone S . Topological orientation of acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) and identification of a putative active site histidine and the role of the n terminus in dimer/tetramer formation. J Biol Chem. 2010; 285(48):37377-87. PMC: 2988343. DOI: 10.1074/jbc.M110.163691. View

5.
Paul D, Bartenschlager R . Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave. Annu Rev Virol. 2016; 2(1):289-310. DOI: 10.1146/annurev-virology-100114-055007. View